2. Field of the Invention
The present invention is directed to novel 4-(1-hydroxy-2-substituted amino)ethyl-5-hydroxy-2(5H)-furanones which are active as anti-inflammatory agents. The present invention is also directed to pharmaceutical compositions which comprise one or more of the novel compounds of the invention, to the methods of using these pharmaceutical compositions, and to the chemical processes of making the novel compounds.
3. Brief Description of the Prior Art
Manoalide is a compound isolated from a marine sponge [E. D. de Silva et al., Tetrahedron Letters 21:1611-1614 (1980)] which has anti-inflammatory, immunosuppressive and analgesic properties. Manoalide (Compound 1) the structure of which is shown below, includes a 5-hydroxy-2(5H)-furanone moiety, attached in the 4-position of the furanone ring to the rest of the molecule. Certain analogs of manolide, such as seco-manoalide (Compound 2) and dehydro-seco-manoalide (compound 3) also have antiinflammatory activity. For further description of the biological activity of manoalide and some of its derivatives reference is made to U.S. Pat. No. 4,447,445 and to European Patent Application No. 0133376 (published on February 20, 1985). ##STR2##
Synthetic analogs of of manoalide, particularly analogs having various substituents on the furanone moiety of manoalide, are described in several applications for United States Letters Patent by the same inventor as in the present application, the following of which have been allowed and are expected to issue as United States Letters Patent:
Ser. No. 259,225 filed on Oct. 18, 1988; PA1 Ser. No. 281,126 filed on Dec. 7, 1988. PA1 a. Bee venom phospholipase A.sub.2 in 10 uM HEPES (pH 7.4) with 1 mM CaCl.sub.2 is incubated with vehicle or test agent for 1.0 hour at 41.degree.. PA1 b. 1 36 mM phosphotidylcholine, 2.76 mM Triton X-100 are dispersed in buffer by sonication and then mixed with L-3 phosphotidylcholine, 1-palmitoyl-2-(1-.sup.14 C) palmitoyl for 10 min. PA1 c. Start the reaction by the addition of enzyme (0.495 units/ml). PA1 d. Incubation for 15 sec. at 41.degree.. PA1 e. Reaction is terminated by addition of 2.5 ml of isopropanol: n-heptane: 0.5 M H.sub.2 SO.sub.4 (40:10:1; v:v:v:). PA1 f. 2 0 ml n-heptane and 1.0 ml H20 added; mixture centrifuged. PA1 g. 2.0 ml n-heptane removed and treated with 200-300 mg of silica gel HR60. PA1 h. Samples centrifuged; 1 ml of n-heptane SN removed and added to 10 ml scintillation fluid. PA1 i. Samples counted on a scintillation counter.
Published European Patent Application No. 0 295 056 discloses 4-substituted 5-hydroxy-2(5H)-furanones having antiinflammatory, immunosuppressive and antiproliferative activity where the substituents in the 4 position are a variety 1-hydroxyalkyl, 1-acyloxy-alkyl and 1-carbamoyloxy-alkyl groups.